Extremities Feature

Is Fracture Healing in Space Problematic?

Tracey Romero • Mon, September 11th, 2017

A team of bioengineers led by the University of Missouri have been thinking a lot about what would happen if an astronaut broke a leg or injured a knee while in space. Can a fracture heal just as well in space as it would on Earth?

In a recent study, Elizabeth Loboa, Ph.D., dean of the College of Engineering at the university and her team that includes researchers from the University of North Carolina and North Carolina State found that the key to that answer is gravity or ‘mechanical loading’.

Mechanical loading or forces that stimulate cellular growth for development, is required for creating cartilage that is then turned to bone but little is known about how cartilage develops in the absence of gravity or mechanical loads.

According to their study findings, microgravity may actually inhibit cartilage formation, complicating the healing process for astronauts who experience a fracture while in space as well as for patients on bed rest or who are paralyzed due to trauma.

“Because these tissues cannot renew themselves, bioreactors, or devices that support tissue and cell development, are used in many cartilage tissue engineering applications. Some studies suggest that microgravity bioreactors are ideal for the process to take place, while others show that bioreactors that mimic the hydrostatic pressure needed to produce cartilage might be more ideal. Our first-of-its-kind study was designed to test both theories,” Loboa said in a release.

The process through which cartilage is developed is called chondrogenic differentiation. Using human adipose, or fat cells (hASC) obtained from women, Loboa and her team tested chondrogenic differentiation in bioreactors that simulated either microgravity or hydrostatic pressure, which is the pressure that is exerted by a fluid.

The results showed that cyclic hydrostatic pressure, which has been shown to be beneficial for cartilage formation, caused a threefold increase in cartilage production and resulted in stronger tissues. Microgravity, in turn, decreased chondrogenic differentiation.

“Our study provides insight showing that mechanical loading plays a critical role during cartilage development,” Loboa said. “The study also shows that microgravity, which is experienced in space and is similar to patients on prolonged bed rest or those who are paralyzed, may inhibit cartilage and bone formation. Bioengineers and flight surgeons involved with astronauts’ health should consider this as they make decisions for regenerating cartilage in patients and during space travel.”

“Cartilage tissue engineering is a growing field because cartilage does not regenerate,” said Elizabeth Loboa, Ph.D., dean of the MU College of Engineering and a professor of bioengineering, in the August 22, 2017 news release.

“Because these tissues cannot renew themselves, bioreactors, or devices that support tissue and cell development, are used in many cartilage tissue engineering applications. Some studies suggest that microgravity bioreactors are ideal for the process to take place, while others show that bioreactors that mimic the hydrostatic pressure needed to produce cartilage might be more ideal. Our first-of-its-kind study was designed to test both theories.”

As MU College of Engineering wrote in the news release, “Using human adipose, or fat cells (hASC) obtained from women, Loboa and her team tested chondrogenic differentiation in bioreactors that simulated either microgravity or hydrostatic pressure, which is the pressure that is exerted by a fluid. Researchers found that cyclic hydrostatic pressure, which has been shown to be beneficial for cartilage formation, caused a threefold increase in cartilage production and resulted in stronger tissues. Microgravity, in turn, decreased chondrogenic differentiation.”

“Our study provides insight showing that mechanical loading plays a critical role during cartilage development,” Dr. Loboa said. “The study also shows that microgravity, which is experienced in space and is similar to patients on prolonged bed rest or those who are paralyzed, may inhibit cartilage and bone formation. Bioengineers and flight surgeons involved with astronauts’ health should consider this as they make decisions for regenerating cartilage in patients and during space travel.”

Dr. Loboa told OTW, “From an orthopedic surgeon’s standpoint, our study shows the benefits of physiological loading to stimulate chondrogenesis. So, if a patient is on prolonged bed rest with a broken leg and no mechanical loading is occurring at the fracture site, then chondrogenesis (cartilage formation) could be delayed or inhibited.

Vibrations Turn Stem Cells Into Bone

Biloine W. Young • Wed, July 20th, 2016

Scientists in Scotland have discovered that they can grow new bone just by vibrating it. As reported by The Telegraph Science Editor Sarah Knapton, stem cells can be coaxed into turning into bone cells—known as osteoblasts—by using low frequency vibrations in the lab. This technique is known as “nanokicking.” The vibrations used are very slight. They are so small that they have been compared to the vibrations caused by sliding a sheet of paper back and forth under a football.

Researchers at the University of West Scotland and the University of Glasgow used a frequency of 1000 Hz. They believe that this frequency may mimic conditions experienced by bone in the body. In the laboratory that frequency stimulated the growth of natural bone in around 28 days.

Knapton quoted Professor Stuart Reid of the University of West Scotland as saying, “Our bodies are continuously experiencing mechanical stimuli, such as from our walking steps and our heart beat. We know that natural bone has some interesting mechanoelectrical properties, the piezoelectric effect—converting mechanical stress to electricity, which are optimal close to 1000Hz.” The researchers hope that this same frequency could be used to encourage healing of damaged bone while it is still within the body.

Reid added, “It is also well known that bone can only remain healthy when it is actively being loaded. That is why astronauts lose bone mass when in space. So we believe that we are mimicking something that the cells experience in our bodies.”

Knapton noted that bone is the second most commonly transplanted tissue in the world, behind blood transplants. The UK doctors are acutely aware that the United Kingdom’s growing population of aging citizens means that demand will increase for treatments for ailments such as osteoporosis and hip fractures.

The team aims to test their lab-grown bone in people within three years. They hope it will be possible to “nanokick” patients directly to heal fractures without surgery. The new technology is being shown at the Royal Society’s Summer Science Exhibition in London.

Major Pro-inflammatory Response With Intra-articular Ankle Fractures

Elizabeth Hofheinz, M.P.H., M.Ed. • Mon, November 16th, 2015

Researchers from Duke University and the University of Rochester have made progress in determining what is going on with patients who have intra-articular fractures and—even after anatomic fracture reduction—develop ankle arthritis.

Twenty-one patients with an intra-articular ankle fracture were included in this study. The research team set out to characterize the inflammatory cytokine and matrix metalloproteinase (MMP) composition in the synovial fluid of patients with these fractures.

Samuel Adams, M.D. is assistant professor of Orthopaedic Surgery and director of Foot and Ankle Research at Duke University Medical Center. He told OTW, “This work was performed because despite excellent reduction of ankle fractures, a large majority of intra-articular fractures develop ankle arthritis. Therefore, there must be other forces at play. This study demonstrated that at the time of injury there is a large pro-inflammatory response in the ankle joint. While this study does not correlate this inflammatory response to ankle arthritis, we hypothesize that this initial inflammation can initiate an inflammatory cascade of cartilage damage and synovitis. Most readers may question the fact that ‘inflammation’ is the first step in healing of all tissues. This is true, but one must remember that the inflammation healing response is intended for the fractured bone and not the healthy cartilage and synovium in the ankle joint that is in direct communication with the fracture healing. I recommend a thorough irrigation of the joint at the time of fracture fixation or a needle or arthroscopic lavage at the time of external fixation to reduce the inflammatory burden.”

$1.1 Million to Study, Speed Bone Regeneration and Repair

Elizabeth Hofheinz, M.P.H., M.Ed. • Thu, June 25th, 2015

New York University Polytechnic School of Engineering, NYU School of Medicine, and Stanford University are the recipients of a $1.1 million grant that will enable them to aid soldiers and civilians alike. With the funds—provided by the U.S. Veterans Health Administration’s Office of Rehabilitation Research and Development—will be targeted towards a new approach that could harness the “body’s chemical signals to speed bone regeneration and improve repair.”

Alesha B. Castillo, Ph.D. is an assistant professor of mechanical and aerospace engineering and orthopedic surgery at New York University. She is working with Philipp Leucht, M.D., an assistant professor in the Departments of Orthopaedic Surgery and Cell Biology at the NYU School of Medicine, and Jill A. Helms, Ph.D., a professor of surgery at Stanford University School of Medicine, in order to focus on one stem-cell recruitment factor found in connective tissue and bone cells—CXCL12 and its receptor.

According to the June 18, 2015 news release, the team hypothesizes that both of these “play key roles in promoting osteogenesis, both in response to injury as well as mechanical stress. Through experiments using genetically modified mice, the team hopes to better define the role of CXCL12 in osteogenesis following mechanical loading as well as its role in bone repair in response to injury. The researchers also plan to explore whether local delivery of CXCL12 can augment the body’s own natural response to bone injury and improve bone repair.”

“If we can mobilize and recruit the body’s own stem cells to aid in repair of serious bone injuries, we would have the basis for a very powerful, next-generation therapy, ” Castillo explained. “Between the aging population, who are prone to major hip fractures, and large numbers of wounded veterans with complex blast injuries, the promise of a non-invasive therapy that can harness the native signaling pathways to help bones heal better is extremely exciting.”

Dr. Castillo told OTW, “We are just beginning this exciting work. Based on our preliminary data, we believe that a stem cell recruitment factor will significantly advance our ability to treat complex injuries with significant tissue deficits in both young and aged bone.”

“The most challenging aspect of conducting this proof-of-principle research is determining the appropriate time to deliver the agent and dosing.

Cartilage Repair Translational Research: Guidelines Being Ignored

Elizabeth Hofheinz, M.P.H., M.Ed. • Fri, October 30th, 2015

What is the use of having recommendations if no one follows them? A team led by researchers from the Perelman School of Medicine at the University of Pennsylvania, has plunged into the issue of regulatory guidance documents and cartilage repair. Indicating in the October 21, 2015 news release that there is “little to no” adherence to the recommendations published by U.S. and European regulatory agencies on how translational research is conducted and reported in large animal models used to study cartilage repair, the researchers undertook an evaluation of 114 large animal studies.

The team analyzed three sets of regulatory guidance documents published by the U.S. Food and Drug Administration, the European Medicines Agency, and the American Society for Testing and Materials. The team looked at cartilage repair studies published over the past two decades and scored the studies based on adherence to 24 categories appearing in the guidance documents (such as animal age and gender, study duration) and to the methods used for determining successful outcomes, and whether a follow-up MRI or clinical evaluation were performed.

“When we started this project, we assumed that there would be strong positive correlation between the publication of the guidance documents and the level of adherence to these guidelines following publication, ” said Robert Mauck, Ph.D., an associate professor of Orthopedic Surgery and Bioengineering and director of Penn’s McKay Orthopaedic Research Laboratory. “However, when we completed our analysis, we were surprised to find that for the large animal studies we examined, most did not follow the guidelines to any great extent. This got us thinking about the reasons behind the lack of adherence, and the steps that could be taken to help the field more closely align with these recommendations.”

The research team also included Christian Pfeifer, M.D., of the Regensburg University Medical Center and Matthew Fisher, Ph.D., of North Carolina State University and the University of North Carolina at Chapel Hill, former postdoctoral fellows in the McKay Orthopaedic Research Laboratory.

Dr. Mauck told OTW, “We were quite surprised to discover that the publication of the guidance documents from regulatory and standards organization had little impact on the field of preclinical large animal models of cartilage repair, and how poor overall the adherence to these guidelines was.